Investigation of Reishi as a Natural Therapeutic for Inflammatory Breast Cancer The proposed study will investigate the in vivo anti-cancer effects of a dietary supplement containing whole mushroom compounds of Reishi on Inflammatory Breast Cancer (IBC) onset and progression. IBC is the most lethal and least understood form of advanced breast cancer. Its lethality originates from its nature of invading the vascular and lymphatic systems and absence of a typical tumor mass. Reishi compounds have been used in cancer to improve the immune system and kill malignant cancer cells. However, the effect of Reishi extract as a natural targeted therapeutic on IBC has not been investigated. Our preliminary data studying a human IBC cell line shows that whole mushroom Reishi extract inhibits IBC progression by affecting genes that contribute to cancer cell survival, invasion, metastasis, and progression. Reishi extract selectively inhibits IBC cell growth and invasion of the tumor environment. Furthermore, Reishi extract inhibits matrix metalloproteinase 2 and 9 secretion, and E-cadherin protein expression, possibly impairing the capacity of tumor spheroid formation that is characteristic of the IBC phenotype, and a requirement for invasion. Our HYPOTHESIS is that Reishi inhibits IBC onset and progression. Our long-term OBJECTIVES are to determine the therapeutic efficacy of whole mushroom Reishi extract, and investigate the molecular mechanisms by which Reishi affects IBC progression. SPECIFIC AIM 1 will determine the in vivo effects of whole mushroom Reishi extract on IBC onset and progression in an immunocompromised mouse model using novel imaging techniques. SPECIFIC AIM 2 will delineate the molecular targets of whole mushroom Reishi extract lymph nodes and primary tumors at the gene and protein level following treatment with placebo or Reishi extract. SPECIFIC AIM 3 will detail the mentoring and career developmental plans for the PI to achieve a successful independent research career. This proposal is UNIQUE in evaluating a role for a dietary supplement in a locally invasive breast cancer. This research is RELEVANT to public health because it promises to advance the understanding and detection of the therapeutic mechanisms of whole mushroom Reishi dietary supplement for this fatal disease and impact IBC patients, those at risk, and survivors of IBC.